晚期NSCLC靶向治疗2015,5,研究生课.ppt

* * ARMS，29种突变 * * * * The timelines for three key Phase III trials with IRESSA in NSCLC are shown here: ISEL1, INTEREST2 and IPASS3,4; INTEREST and IPASS were the two pivotal studies for the EU submission. IRESSA was first registered for NSCLC in 2002 but the significance of biomarkers and in particular EGFR mutations was discovered relatively late in its development. Early in development it was possible to show that there was complete inhibition of EGFR receptor signalling by the drug. Following the results from ISEL, a trial in a very refractory patient population, it became clear that it was not just necessary to inhibit the target but to find out if the growth of the tumour was truly dependent on the target. It should be noted that both ISEL and INTEREST were in an unselected patient population and were both initiated before the identification and biological significance of EGFR mutations was understood. FISH analysis was incorporated as a co-primary endpoint in the INTEREST trial to analyse EGFR-gene copy number. IPASS was the first and only trial in which patients were selected for treatment on the basis of clinical characteristics. It was designed shortly after the reporting of the ISEL results. Patient selection in the IPASS trial was based on clinical characteristics because, at the time, there was no clear candidate for a biomarker on which to recruit a large PhIII trial and the understanding of the significance of EGFR mutations and the methodology for detection was still evolving. This selection process gave a clinical population in which 60% of the patients in IPASS were ultimatley identified as being EGFR mutation positive. References 1. Thatcher et al. Lancet 2005; 366:1527-1537 2. Kim et al. Lancet 2008; 372: 1809–1818. 3. Mok et al. NEJM 2009; 361: 947-957. 4. Fukuoka M et al. J Clin Oncol 2009; 25 (15s suppl) Abs 8006. 首先我们来看奠定易瑞沙作为突变患者一线标准治疗的关键性III期研究，IPASS研究。这是一项比较易瑞沙与卡铂/紫杉醇一线治疗不或少吸烟的亚裔晚期NSCLC腺癌患者的前瞻性、多中心、随机、开放、III期临床研究，研究由全部来自亚洲地区的中心共同参与，因此也